Revised Abstract: DESCRIPTION (provided by applicant): If the immune deficiency associated with allogeneic hematopoietic stem cell transplantation (HSCT) could be corrected or even prevented, the therapeutic index of allogeneic HSCT would be significantly improved and its impact greatly enhanced. Our hypothesis is that understanding the pathways that regulate early T cell development, maturation, differentiation, and acquisition of function coupled with the development and clinical translation of specific approaches to enhance each of these steps while controlling alloreactivity will be necessary to achieve this objective. Over the past 2 years, an international team of experts composed of stem cell biologists, basic and clinical immunologists, transplant biologists, transplant clinical investigators, and biostatisticians has been assembled to attack this problem. Each of these individuals brings a strong translational track record and commitment to this challenge. Our goal is to develop translational strategies to foster rapid and, if possible, complete immune reconstitution after HSCT in order to eliminate the multiple complications that accompany acute and chronic immune deficiency. We propose to develop, enable, and standardize these technologies which will in turn impact favorably on GVHD, regimen-related toxicity, and relapse. To this end, seven Projects and five Cores have been developed. Projects 1 and 2 will study the common lymphoid progenitor cell in mice and humans in order to develop strategies to enhance HSCT immune reconstitution. Projects 3 and 4 will attempt to prevent and/or repair HSCT associated thymic damage in murine models and translate these strategies to patients undergoing allogeneic HSCT. Project 5 will attempt to reduce the intensity of conditioning regimens by using veto and regulatory cells to control host anti-donor alloreactivity. This approach has the potential to improve immune reconstitution. Project 6 will attempt to improve ex vivo strategies to anergize donor anti-host alloreactive T cells to control GVHD thereby allowing a broad functional T cell repertoire to be adoptively transferred to HSCT patients. Project 7 will adoptively transfer of alloreactive NK cells following HSCT in order to reduce the intensity of conditioning and tumor relapse. Project 7 also proposes to adoptively transfer T cells of both narrow and broad repertoire to control pathogens. These Projects rely upon the Clinical Trials, Immune Assessment, Biostatistical, Tetramer, and Administrative Cores to provide a platform to foster and facilitate planning, translation, and collaboration. We see this Program as a catalyst to bring others in the field together. The next decade will test the concept whether specific manipulation of the immune system to treat human disease is sound and we are confident that this Program will significantly contribute to this effort.